Androgens define a broad class of steroid hormones that control primarily the development and maintenance of male characteristics. They exert their physiological effects through the androgen receptor (AR), a member of the steroid hormone nuclear receptor superfamily. The AR is activated by binding an androgen (e.g., testosterone) or a related ligand. Activated AR triggers a signal transduction pathway that drives increased transcription of a number of “androgen-responsive” target genes, e.g., prostate specific antigen (PSA). Of note, the signal transduction steps in this pathway have not been fully elucidated.
AR activation by androgens, followed by increased androgen-responsive target gene transcription, stimulates a number of diseases, e.g., prostate cancer. Thus, treating prostate cancer usually includes administering an AR antagonist. Unfortunately, its effectiveness is frequently short-lived, as the AR expressed by cancer cells often becomes androgen-independent, i.e., constitutively active (e.g., due to a mutation). Consequently, the ligand-independent AR drives a high level of target gene transcription that supports persistent cancer growth even in the presence of an AR antagonist.
Thus, there is a need for compositions that modulate androgen-responsive target gene transcription at a signal transduction step downstream of AR activation, as well as methods for their identification and therapeutic use.